Pj. Miettinen et al., Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors, DEVELOPMENT, 127(12), 2000, pp. 2617-2627
Pancreatic acini and islets are believed to differentiate from common ducta
l precursors through a process requiring various growth factors. Epidermal
growth factor receptor (EGF-R) is expressed throughout the developing pancr
eas. We have analyzed here the pancreatic phenotype of EGFR deficient (-/-)
mice, which generally die from epithelial immaturity within the first post
natal week. The pancreata appeared macroscopically normal. The most strikin
g feature of the EGF-R (-/-) islets was that instead of forming circular cl
usters, the islet cells were mainly located in streak-like structures direc
tly associated with pancreatic ducts. Based on BrdU-labelling, proliferatio
n of the neonatal EGF-R (-/-) beta-cells was significantly reduced (2.6+/-0
.4 versus 5.8+/-0.9%, P<0.01) and the difference persisted even at 7-11 day
s of age. Analysis of embryonic pancreata revealed impaired branching morph
ogenesis and delayed islet cell differentiation in the EGF-R (-/-) mice. Is
let development was analyzed further in organ cultures of E12.5 pancreata,
The proportion of insulin-positive cells was significantly lower in the EGF
-R (-/-) explants (27+/-6 versus 48+/-8%, P<0.01), indicating delayed diffe
rentiation of the beta cells. Branching of the epithelium into ducts was al
so impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduce
d 20% in EGF-R (-/-) late-gestation pancreata, as measured by gelatinase as
says. Furthermore, the levels of secreted plasminogen activator inhibitor-1
(PAI-1) were markedly higher, while no apparent differences were seen in t
he levels of active uPA and tPa between EGF-R (-/-) and wild-type pancreata
, Our findings suggest that the perturbation of EGF-R-mediated signalling c
an lead to a generalized proliferation defect of the pancreatic epithelia a
ssociated with a delay in beta cell development and disturbed migration of
the developing islet cells as they differentiate from their precursors. Upr
egulated PAI-I production and decreased gelatinolytic activity correlated t
o this migration defect. An intact EGF-R pathway appears to be a prerequisi
te for normal pancreatic development.